Drug resistance in canine heartworm (Dirofilaria immitis): Surveillance in Australia and global genomic insights

Abstract

Heartworm disease caused by Dirofilaria immitis is a potentially fatal condition affecting Carnivora species globally. To prevent this disease, the veterinary industry has relied heavily on the macrocyclic lactone (ML) drug class. However, widespread use of these drugs has led to resistance in the USA. In Australia, there are growing suspicions of potential drug resistance, but only limited testing has been conducted. The enigmatic origins, history, and current population structure of this parasite in Australia further hinder our ability to understand the likelihood and rate at which resistance may develop and spread. This thesis aimed to use phenotypic and genotypic tools to uncover the potential presence of drug-resistant heartworms in Australia, while elucidating their cryptic origins and genomic background. Modified Knott’s tests on a cohort of dogs from QLD and New South Wales (NSW) revealed sub-optimal microfilaremia reductions (≤90%) ~30 days post-ML treatment in 16 of 22 dogs, suggesting potential drug resistance. This was further supported by reductions of <40% in two dogs from Townsville, Australia using the microfilarial suppression test. Although these dogs initially showed sub-optimal reductions, their microfilaremia eventually cleared after an extended period of time. Despite these findings, genetic screening of microfilariae demonstrated no resistance-associated signatures from the USA. Global genome-wide analysis of 127 adult heartworms from four continents revealed genetically distinct populations on each continent, indicating that USA resistance markers are likely non-informative elsewhere. Finally, the study found Australian heartworms are of Asian origin and likely entered the country with dingoes. The outcomes of this thesis not only shed light on the intriguing history of heartworms and the potential emergence of drug resistance in Australia, but have broader global applications that can assist in the future control of this expanding parasite.